Natural saccharide-binding proteins, including lectins and periplasmic substrate-binding proteins, use water desolvation, hydrogen bonding (H-bonding), and C—H• • •π interactions to selectively recognize glycans that may differ only by the orientation of a single hydroxyl group to achieve binding affinities, Kas, as high at 106 M−1 (ESSENTIALS OF GLYCOBIOLOGY (Ajit Varki et al. eds., Cold Spring Harbor Laboratory Press 1999); BEAT ERNST et al., CARBOHYDRATES IN CHEMISTRY AND BIOLOGY PART II: BIOLOGY OF SACCHARIDES (Wiley-VCH 2000); Ambrosi et al., Org. Biomol. Chem. 3:1593-1608 (2005); Toone, Curr. Opin. Struct. Biol. 4:719-728 (1994); Lemieux, Acc. Chem. Res. 29:373-380 (1996)). Selective carbohydrate recognition with artificial receptors remains a major area of investigation because of the challenge of differentiating between molecules with subtle structural differences, their ability to reveal fundamental aspects of saccharide binding, and their potential applications in disease detection, therapy, or catalysis (Davis, Org. Biomol. Chem. 7:3629-3638 (2009); Davis & Wareham, Angew. Chem. Int. Ed. 38:2978-2996 (1999); Mazik, RSC Adv. 2:2630-2642 (2012); Mazik, Chem. Soc. Rev. 38:935-956 (2009); Kubik, Angew. Chem. Int. Ed. 48:1722-1725 (2009); Jin et al., Med. Res. Rev. 30:171-257 (2010); Walker et al., Cell. Mol. Life Sci. 66:3177-3191 (2009)). These receptors employ both covalent and noncovalent interactions to stabilize complexation. For example, the reversible reaction of boronic acids to syn-diols has been employed successfully to selectively bind sugars, such as glucose and ribose, and sugar alcohols, like sorbitol and mannitol (Jin et al., Med. Res. Rev. 30:171-257 (2010); TONY D. JAMES et al., BORONIC ACIDS IN SACCHARIDE RECOGNITION (The Royal Society of Chemistry 2006); James et al., Angew. Chem. Int. Ed. 35:1910-1922 (1996)), but the recognition of monosaccharides possessing axial hydroxyl groups, such as mannose, remains challenging by this approach. Alternatively, by following Cram's principles of electronic complementarity and structural preorganization (D. J. CRAM & J. M. CRAM, CONTAINER MOLECULES AND THEIR GUESTS (The Royal Society of Chemistry 1997); Artz & Cram, J. Am. Chem. Soc. 106:2160-2171 (1984); Cram et al., J. Am. Chem. Soc. 103:6228-6232 (1981); D. J. Cram and J. M. Cram, Acc. Chem. Res. 11:8-14 (1978)), molecules were created that bind through only noncovalent interactions and do not distort significantly upon binding. In these receptors, recognition groups are rigidly positioned in three dimensional space, like natural lectins (Weis & Drickamer, Annu. Rev. Biochem. 65:441-473 (1996)), to overcome entropy-enthalpy compensation whereby any favorable enthalpic change that arises from the formation of noncovalent bonds is offset by the entropically unfavorable decrease of the internal motions of host and guest upon binding (Liu & Guo, Chem. Rev. 101:673-695 (2001)).
Noteworthy examples of preorganized synthetic saccharide receptors that bind through only noncovalent interactions are the “temple” family of hosts developed by Davis and coworkers and the “tripodal” receptors pioneered by the Roelens (Arda et al., Chem. Eur. J. 17:4821-4829 (2011); Cacciarini et al., Org. Biomol. Chem. 9:1085-1091 (2011); Nativi et al., Chem. Eur. J. 17:4814-4820 (2011); Arda et al., Eur. J. Org. Chem. 2010:64-71 (2010); Arda et al., Chem. Eur. J. 16:414-418 (2010); Nativi et al., J. Am. Chem. Soc. 129:4377-4385 (2007); Nativi et al., Org. Lett. 9:4685-4688 (2007); Cacciarini et al., J. Org. Chem. 72:3933-3936 (2007); Vacca et al., J. Am. Chem. Soc. 126:16456-16465 (2004)) and Mazik groups (Mazik & Buthe, Org. Biomol. Chem. 6:1558-1568 (2008); Mazik & Hartmann, J. Org. Chem. 73:7444-7450 (2008); Mazik et al., Chem. Eur. J. 15:9147-9159 (2009); Mazik & Sonnenberg, J. Org. Chem. 75:6416-6423 (2010); Mazik & Geffert, Org. Biomol. Chem. 9:2319-2326 (2011)). The temple receptors position polar amidopyridine groups between apolar aromatic surfaces, and these receptors are highly selective for mono- and disaccharides containing all equatorial hydroxide groups, such as β-glucose (Glc) (Barwell et al., Angew. Chem. Int. Ed. 48:7673-7676 (2009)), β-N-acetylglucosamine (GlcNAc) (Ferrand et al., Angew. Chem. Int. Ed. 48:1775-1779 (2009)), and β-D-cellobioside (Sookcharoenpinyo et al., Angew. Chem. Int. Ed. 51:4586-4590 (2012); Ferrand et al., Science 318:619-622 (2007)) in water. The tripodal receptors rely upon a 1,3,5-triethylbenzene scaffold to rigidly orient three aminopyrrolitic arms that can form hydrogen bonds with saccharide hydroxyl groups. The preorganization induced by the three ethyl arms add an estimated 4.5 kcal mol−1 in additional stabilization upon complexation (Stack et al., J. Am. Chem. Soc. 115:6466-6467 (1993)). The tripodal receptors bind strongly to glycosides with an affinity of 102 to 105 M−1 in chloroform and acetonitrile, and by changing to a chiral diaminopyrrolic motif, high selectivity for octylmannosides in acetonitrile has been observed, ranging from 1:7 β-GlcNAc:α-Man to 1:38 α-Gal:β-Man (Nativi et al., Chem. Eur. J. 17:4814-4820 (2011)). Mannose is a particularly interesting monosaccharide target, because it is a biomarker for several cancers (de Leoz et al., Mol. Cell. Proteomics 10:M110.002717 (2011); Ann et al., Curr. Opin. Chem. Biol. 13:601-607 (2009)), and as a consequence developing mannose specific synthetic receptors remains an active area of research (Arda et al., Chem. Eur. J. 17:4821-4829 (2011); Nativi et al., Chem. Eur. J. 17:4814-4820 (2011); Arda et al., Eur. J. Org. Chem. 2010:64-71 (2010); Arda et al., Chem. Eur. J. 16:414-418 (2010); Nativi et al., Org. Lett. 9:4685-4688 (2007); Nakagawa et al., J. Am. Chem. Soc. 133:17485-17493 (2011)). However, synthetic carbohydrate receptors with increased binding affinity, expanded substrate scope beyond all-equatorial glycosides, and increased selectivity to levels comparable with their biological counterparts are still needed before these receptors become more widely utilized.